Aging is associated with a general loss of ability to modulate responses to a physiological stress. The mechanisms underlying the loss of the capacity of the aging organism to cope with stress are unclear, but evidence implicates increased generation of reactive oxygen species (ROS) and associated oxidative stress. Using electron paramagnetic resonance spectroscopy the investigators have demonstrated that in both young and old rats heat stress quantitatively increases nitric oxide and ROS generation, leading to oxidative tissue injury. They have also demonstrated that older rats are significantly less thermotolerant to repeated heat challenge than young rats and are less capable of generating protective stress proteins. Pilot studies establish that following heat stress, both ROS production and mortality rates are exaggerated in senescent versus young rats. Thus, the guiding hypothesis for this research program is that aging organisms have a reduced ability to cope with physiological stress due to an exaggerated production of ROS and concomitant oxidative damage. They will examine this hypothesis by: 1) determining if ROS production and oxidative injury are exaggerated, and as a consequence, morbidity and mortality rates are increased following heat stress in senescent versus mature and young conscious rats; 2) elevating antioxidant capacity in older rats to reduce the level of oxidative stress with the goal of achieving lower morbidity and mortality rates; and 3) determining if the loss of transcriptional regulation of important stress-induced genes occurs in aged rats. They will use an integrated approach that includes whole animal, cellular, molecular, and novel in vivo gene transfer techniques that overexpress antioxidant enzymes to pursue basic mechanisms in the stress response. By using a variety of state-of-the-art techniques, the intent is to be able to address important mechanistic questions involving free radical formation, oxidant stress, and aging that will have application to numerus clinical problems (heat stoke, septic shock, cardiovascular disease, diabetes, frailty, etc.) in the aged population.